1. Field of the Invention
This invention relates to novel pyridazine-containing thioamide derivatives having high gastric anti-secretory activity and represented by the formula: ##STR3## wherein R.sub.1 is a group having a pyridazine skeleton with or without a substituent, R.sub.2 is hydrogen or methyl, R.sub.3 is hydrogen, methyl or phenyl, R.sub.4 is hydrogen or methyl, and n is zero or 1. The group R.sub.1 is represented by ##STR4## wherein A is hydrogen, methyl, phenyl or mercapto, and B is hydrogen or phenyl.
2. The Prior Art
As is well known, G. D. Searle & Co. in 1967 developed 2-phenyl-2-(2-pyridyl)thioacetamide (SC-15396) as an antigastrin agent having anti-ulcer activity (D. L. Cook, R. G. Bianchi, Life Sci., 6 1381, 1964). Concurrently various analogous compounds were developed (R. G. Bianchi, D. L. Cook, Federation Proc., 27, 1331, 1968; Belg., 669,165 (1966); Ger. Offen., 1,934,392 (1970); Ger. Offen. No. 2,188,331 (1972); U.S. Pat. No. 3,624,085; 3,686,190).
Along with the synthesis of such active compounds, advanced research was conducted on the correlation between gastric antisecretory effects and chemical structural formulae, leading to the conclusion that thioacetamide is of significance as a group for producing the desired activity (C. E. Malen, B. H. Danree, X. B. L. Pascaud, J. Med. Chem., 14 (13), 244, 1971, J. M. Bustard Y. C. Martin, J. Med. Chem., 15 (11), 1101 1972). Directing attention to the reduced side effects and remarkably sustained activity of thioamide derivatives containing a pyridazine skeleton, we carried out research on the synthesis of such thioamide derivatives despite the difficulties encountered in the preparation thereof and the complexity of the process required. Our efforts have resulted in this invention.
The pyridazine-containing thioamide derivatives of this invention represented by the formula (I) are prepared from nitrile derivatives or acid amide derivatives, which are obtained by the following methods. (1) Nitrilepyridazine derivatives (II) are synthesized by preparing a 3-halogenopyridazine derivative according to the method disclosed in A. Staehelin, K. Eichenberger, J. Druey, Helv. Chem. Acta., 39, 1741, 1956 and reacting benzylcyanide with the derivative as represented by the following equation in the process of sodium amide. ##STR5## (2) Although it is known to synthesize 2-pyridazinyl alkylcyanide by Hensell's method (H. P. Hensell, H. Bauman, B.P. 946,471 (1961) or Feuer's method (J. Feuer, J. Am. Chem. Soc., 80, 5877, 1958), we have found a novel method of synthesizing nitrile derivatives (III) or acid amide derivatives (IV) by reacting an acrylonitrile derivative or acrylamide derivative with a 6-suubstituted-3-oxo-(2H)pyridazine as expressed by the following equation in the presence of a catalytic amount of Triton-B (trimethyl benzylammonium hydroxide, 40% methanol solution). ##STR6## (3) Compounds (V) having lactumthicketone are synthesized by reacting a 3-oxo-2-pyridazinylalkylnitrile with phosphorous pentasulfide as represented by the following equation. ##STR7##
The compounds (I) according to this invention are prepared from the starting materials described above by the following processes.
(1) 6-Substituted-3-pyridazinylthioacetamides (IA) are prepared by reacting hydrogen sulfide with a nitrile derivative (II) as dissolved in pyridine in the presence of pyrrolidine or triethylamine serving as a catalyst. ##STR8##
However, 2-phenyl-2-(6-mercapto-3-pyridazinyl)-thioacetamide is prepared from 2-phenyl-2-(6-chloro-3-pyridazinyl)acetonitrile.
(2) 2-Pyridazinyl-alkylthioacetamides (IB) are prepared by reacting a nitrile derivative (III) or an acid amide derivative (IV) with phosphorus pentasulfide in pyridine. ##STR9## (3) 3-Thio-2-pyridazinyl-alkylthioacetamides (IC) are prepared by reacting hydrogen sulfide with a nitrile derivative (V) as dissolved in pyridine in the presence of pyrrolidine or triethylamine serving as a catalyst. ##STR10##
The compounds (I) of this invention prepared by the foregoing processes include those listed in Table I below.
TABLE 1 ______________________________________ ##STR11## Compound No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 n ______________________________________ IA-1 ##STR12## -- C.sub.6 H.sub.5 H 0 IA-2 ##STR13## -- C.sub.6 H.sub.5 H 0 IA-3 ##STR14## -- C.sub.6 H.sub.5 H 0 IA-4 ##STR15## -- C.sub.6 H.sub.5 H 0 IB-1 ##STR16## H H H 1 IB-2 ##STR17## H H H 1 IB-3 ##STR18## H H CH.sub.3 1 IB-4 ##STR19## CH.sub.3 H CH.sub.3 1 IC-1 ##STR20## H H H 1 IC-2 ##STR21## H CH.sub.3 H 1 ______________________________________
Most of the compounds of formula (I) were found to have an excellent gastric antisecretory activity, which was evaluated in the 4 hours pylorus ligated rate according to Shay's method (H. Shay, D. C. H. Sun and M. Gruenstein, Gastroenterology, 21 906, 1954).